This activity is designed for nephrologists, endocrinologists, diabetologists, and primary care physicians. No prerequisites required.

LEARNING OBJECTIVESThe Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity. At the conclusion of this activity, the participant should be able to:

Review the impact/prevalence of diabetic microvascular complications and the pathogenesis of diabetic nephropathy.

Implement integrated strategies with physicians in other disciplines for the appropriate screening and early detection of diabetic nephropathy.

Identify the early clinical evidence of diabetic nephropathy.

Review the mechanisms of action of current and future therapies.

Evaluate evidence for emerging therapeutic options.

ACCREDITATION STATEMENTThe Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

CREDIT DESIGNATION STATEMENTThe Johns Hopkins University School of Medicine designates this educational activity for a maximum of 2 category 1 credits toward the AMA Physician's Recognition Award. Each physician should claim only those credits that he/she actually spent in the activity. The estimated time to complete this educational activity: 2 hours.

Release date: January 15, 2005. Expiration date: January 15, 2007.

DISCLAIMER STATEMENTThe opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of The Johns Hopkins University School of Medicine name implies review of educational format, design, and approach. Please review the complete prescribing information of specific drugs or combinations of drugs, including indications, contraindications, warnings, and adverse effects, before administering pharmacologic therapy to patients.

This program is supported by an educational grant from Eli Lilly and Company.

Full Disclosure Policy Affecting CME Activities:As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of Johns Hopkins University School of Medicine to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a sponsor has with the manufacturer(s) of any commercial product(s) discussed in an educational presentation. The Program Director and Participating Faculty reported the following:

PROGRAM DIRECTOR

Donna I. Myers, MDAssistant Professor of MedicineDivision of NephrologyJohns Hopkins University School of MedicineBaltimore, Maryland• Dr Myers reports having no significant financial or advisory relationships with corporate organizations related to this activity.

PARTICIPATING FACULTY

Ekta Bhardwaj, MDDepartment of MedicineManchester Royal Infirmary University of ManchesterManchester, UK• Dr Bhardwaj reports having no significant financial or advisory relationships with corporate organizations related to this activity.

Anthony J. Freemont, MDDepartment of Pathological ScienceManchester Royal Infirmary University of ManchesterManchester, UK• Dr Freemont reports having no significant financial or advisory relationships with corporate organizations related to this activity.

George L. King, MDDirector of ResearchResearch Division and Section HeadVascular Cell BiologyJoslin Diabetes CenterProfessor of MedicineHarvard Medical SchoolBoston, Massachusetts• Dr King reports receiving grants/research support from Eli Lilly and Company; and serving as a consultant to Pfizer Inc.

Rayaz A. Malik, MB.ChB, PhD, MRCPDepartment of MedicineManchester Royal Infirmary University of ManchesterManchester, UK• Dr Malik reports having no significant financial or advisory relationships with corporate organizations related to this activity.

Ralph Rabkin, MDProfessor of MedicineDivision of NephrologyDepartment of MedicineStanford University School of MedicineStanford, California• Dr Rabkin reports having no significant financial or advisory relationships with corporate organizations related to this activity.

Katherine Tuttle, MDDirector of ResearchThe Heart Institute of SpokaneSpokane, Washington• Dr Tuttle reports receiving grants/research support from and serving as a consultant to Eli Lilly and Company.

Richard W. Whitehouse, MDDepartment of RadiologyManchester Royal InfirmaryUniversity of ManchesterManchester, UK• Dr Whitehouse reports having no significant financial or advisory relationships with corporate organizations related to this activity.

Notice: In accordance with the ACCME Standards for Commercial Support, the audience is advised that one or more articles in this continuing medical education activity may contain reference(s) to unlabeled or unapproved uses of drugs or devices. The following faculty members have disclosed that their articles have referenced the following unlabeled/unapproved uses of drugs or devices:

Dr Ohshiro, Ms Lee, and Dr King—ruboxistaurin.

All other faculty have indicated that they have not referenced unlabeled/unapproved uses of drugs or devices.

Advanced Studies in Medicine provides disclosure information from contributing authors, lead presenters, and participating faculty. Advanced Studies in Medicine does not provide disclosure information from authors of abstracts and poster presentations. The reader shall be advised that these contributors may or may not maintain financial relationships with pharmaceutical companies.

Nephropathy is one of the most common diabetic microvascular complications and is a leading cause of morbidity and mortality. Initially, diabetic nephropathy (DN) is characterized by glomerular hemodynamic abnormalities that lead to glomerular hyperfiltration. Over time, these abnormalities lead to progressively increasing glomerular damage: microalbuminuria, overt proteinuria, decreased glomerular filtration rate, and renal failure. Without specific intervention, patients with type 1 diabetes and overt DN (urine protein ³300 mg/24 hours) typically progress to end-stage renal disease (ESRD) within 10 to 20 years.

Studies have proven that timely treatment of developing renal abnormalities can attenuate the progression of DN to ESRD; this underscores the importance of screening and early diagnosis of diabetic nephropathy. Meanwhile, research continues into the biochemical pathways involved in the pathogenesis of diabetic nephropathy, including the polyol pathway, the formation of advanced glycation end-products, generation of oxidative stress, and protein kinase-C (PKC) activation. As our medical understanding of the different pathways of pathogenesis moves forward, new therapeutic targets are emerging, and new treatments are being developed to act on these targets. Currently, drugs that interfere with PKC activation, including ruboxistaurin, are particularly promising.

This issue of Advanced Studies in Medicine highlights various aspects of DN. A review article by Yuzuru Ohshiro, MD, PhD, Yvonne Lee, and George King, MD, discusses the current theories regarding the pathogenesis of DN, focusing particularly on the role of PKC activation. Each of the biochemical pathways described has shown evidence of a generation of toxic and reactive metabolites that lead to alterations in several key signaling intracellular pathways. Therefore, potential interventions, such as antioxidants or advanced glycation end-product inhibitors, are being tested to neutralize toxins. Interventions that block the cellular signaling pathways that mediate the toxic effects of glucose and its metabolites are also being investigated. In addition to hyperglycemia, other factors that accelerate the progression of DN, including hypertension, activation of the renin-angiotensin system, increased expression of fibrotic factors, and increased expression of vascular endothelial growth factor, may also represent potential therapeutic targets.

Early diagnosis and treatment can prevent or limit the progression of DN, emphasizing the importance of appropriate and timely evaluation of renal abnormalities in diabetes mellitus. In her article, Katherine Tuttle, MD, discusses the 3 common methods of screening used to detect microalbuminuria, including the measurement of albumin-to-creatinine ratio in random spot collection, a 24-hour urine collection with creatinine, and a timed (4 hours or overnight) collection. She examines the current guidelines and the issues surrounding screening for DN, discusses the prediction of progression of nephropathy, and provides an algorithm for primary care diagnosis of renal disease. In her case study, Dr Tuttle illustrates the all-too-common comorbidities of diabetes mellitus (nephropathy and cardiovascular disease), providing a treatment plan for management of current symptoms, in addition to reduction of future risk.

In his interview with Advanced Studies in Medicine, Ralph Rabkin, MD, shares a clinicianÕs viewpoint regarding the importance of early detection of microalbuminuria and studies that link the pathogenesis of DN to hyperglycemia. He discusses the timing of drug therapy and the effectiveness, safety, and tolerability of agents currently available. Dr Rabkin also explains the role of diet, exercise, and other lifestyle modifications in managing diabetic nephropathy and discusses the special considerations in the management of the patient with diabetes with impaired kidney function. In his case study, Dr Rabkin provides a clinical profile of a patient with diabetes, renal disease, and hyporeninemic hypoaldosteronism, a combination of comorbidities that alter the typically expected treatment regimen.

In the case study by Rayaz A. Malik, MB.ChB, PhD, MRCP, Ekta Bhardwaj, MD, Richard W. Whitehouse, MD, and Anthony J. Freemont, MD, is presented a patient with type 1 diabetes mellitus who is admitted to the renal ward with acute-onset pain and swelling in his right gastrocnemius muscle and deterioration in his renal function. Dr Malik et al review considerations in the differential diagnosis, in addition to diagnostic techniques, before discussing appropriate management. This case study illustrates some of the challenges in the management of diabetic microvascular complications caused by diabetes mellitus.

Currently, the strongest predictor of beneficial outcome remains individual glycemic control coupled with regular screening examinations for early detection of DN and timely intervention. However, as research efforts focus on the biochemical pathways involved in DN, the therapeutic options are likely to expand, offering patients with diabetes new hope for better outcomes and a better quality of life.

*Assistant Professor of Medicine, Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland.